Breyanzi: CAR T-cell Therapy Gets Positive CHMP Opinion for R/R Large B-Cell Lymphoma Manali Kamdar MD
By Manali Kamdar, MD from University of Colorado
In March of this year, Bristol Myers Squibb announced that the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) had approved the use of Breyanzi, also known as Lisocabtagene Maraleucel, for the treatment of adult patients with diffuse large B-cell lymphoma, high-grade B-cell lymphoma, primary mediastinal large B-cell lymphoma, and follicular lymphoma grade 3B who had relapsed within 12 months of completing or were refractory to first-line chemo-immunotherapy. I believe this positive CHMP opinion is an extremely important milestone and a step forward in making Lisocabtagene Maraleucel a potential new standard of care for patients, especially in the European Union, living with relapsed or primary refractory large B-cell lymphoma.
This is a critical area of unmet need where very few patients can undergo or derive long-term benefit from a stem cell transplant. Therefore, I believe this is a very important milestone forward. Breyanzi or Lisocabtagene Maraleucel is slightly different from the other CAR T-cell therapies currently available.
Lisocabtagene Maraleucel, also known as Liso-cel, is a type of personalized cell therapy that uses chimeric antigen receptors (CARs) to target CD19 cells. It is composed of a defined mixture of CD8 and CD4 CAR T-cells, which are administered at equal and specific doses. In terms of the expected timeline for Breyanzi to receive final approval from the EMA, the European Commission usually delivers its final decision within approximately two months following receipt of the CHMP opinion. This decision will be applicable to all EU member states, as well as Iceland and Norway.
The positive decision was based on data from the TRANSFORM study, which is a phase 3 randomized, global, open-label study that compared Lisocabtagene Maraleucel to standard of care in patients who were primary refractory or had relapsed diffuse large B-cell lymphoma within the first 12 months of frontline chemo-immunotherapy.
The landscape of relapse in free-diffused large B-cell lymphoma did not have many options before. Typically, transplant-eligible patients who failed frontline chemo-immunotherapy attempted salvage chemotherapy, followed by autotransplant for responders. Unfortunately, not all relapses are created equal, and we now know that patients who are primary refractory or relapse within 12 months of receiving chemotherapy are at the highest risk.
These patients seldom benefit from autotransplant, with their overall survival being less than six months. Lisocabtagene Maraleucel, based on the TRANSCEND study, was approved in the third-line setting, including for patients who failed an autotransplant. Thus, it was intuitive to compare it head-to-head with autotransplant and create the TRANSFORM study, a phase 3 study that randomized patients to either standard of care (salvage chemotherapy followed by autotransplant for responders) or Lisocabtagene Maraleucel.
The global study was conducted across 47 sites, enrolling patients from 2018 to 2020. Thirty-two patients were screened, and 184 patients were randomized to receive either Lisocabtagene or standard of care. Patients receiving Lisocabtagene were able to receive bridging therapy, and about 63% of them received one of the three regimens included in salvage chemotherapy.
Crossover was permitted in this study, and the primary progression and endpoint was event-free survival. Secondary endpoints included progression-free survival, overall survival, overall response rate, and patient-reported outcomes, among others.
At the prespecified interim analysis of 6 months, the median event-free survival was significantly improved in the Liso-cel group versus the standard of care group. The median event-free survival was 10 months in the Liso-cel group versus only 2.3 months in the standard of care group. The most common grade 3 or worse adverse events were neutropenia, which occurred in approximately 80% of the Liso-cel group versus 51% of the standard of care group. However, this did not translate into a higher risk of febrile neutropenia, which was actually higher in the autotransplant group.
Serious treatment-emergent adverse events were reported in 48% of the Liso-cel group versus 48% of the standard of care group. It is important to note that there were no grade 4 or 5 CRS or neurological events reported in the Liso-cel arm.
Most of the toxicities were low grade (grades 1 and 2). 48% of patients in the Liso-cel group experienced CRS, and only 7% experienced grade 3 neurological toxicity.
At the primary analysis, which occurred at the 17.5-month mark, the median event-free survival was not reached in the Liso-cel arm versus only 2.4 months in the standard of care arm. The median progression-free survival was also not reached in the Liso-cel arm versus only 6.2 months in the standard of care arm.
The overall response rate and complete response rate were higher and statistically significant compared to the standard of care arm. The overall response rate was 87% in the Liso-cel arm versus only 49% in the standard of care arm. The complete response rate was 74% in the Liso-cel arm versus 43% in the standard of care arm.
It is important to note that the median overall survival was not reached in the Liso-cel arm versus 29.9 months in the standard of care arm. Crossover was permitted, so it was difficult to establish overall survival. However, when adjusted for crossover from standard of care to Liso-cel, the 18-month overall survival rates were 73% for Liso-cel versus only 54% for standard of care.
Based on the TRANSFORM study, these data show significant improvements in event-free survival, complete response rate, and progression-free survival for Liso-cel compared to standard of care. These results support Liso-cel as the preferred second-line treatment for patients who are primary refractory or who have relapsed with large B-cell lymphoma within 12 months after frontline chemo-immunotherapy.
I believe some of the pivotal studies in Liso-cel were the TRANSFORM study, a phase 3 trial in transplant-fit patients with high-risk, relapsed, refractory aggressive large B-cell lymphoma, and the PILOT study, a phase 2 trial that tested Lisocabtagene Maraleucel in patients with relapsed diffuse large B-cell lymphoma who were ineligible for transplant. Based on these studies, the FDA approved Lisocabtagene Maraleucel for patients who are transplant eligible and have primary refractory or relapse refractory DLBCL within 12 months of chemo.
The FDA also approved Lisocabtagene Maraleucel for patients who are transplant ineligible and have relapsed diffuse large B-cell lymphoma after one line of treatment, irrespective of the timing of relapse. I believe this provides a huge unmet need, not only for high-risk transplant-eligible patients but also for transplant-ineligible patients who cannot tolerate more chemotherapy or intense treatment. The PILOT study data showed that Lisocabtagene Maraleucel was very well tolerated.
Lisocabtagene Maraleucel is clearly changing the treatment landscape for patients with relapsed refractory large B-cell lymphoma, demonstrating excellent outcomes. However, there are other subtypes of lymphomas that need improved treatments, such as relapsed mantle cell lymphoma, relapsed follicular lymphoma, and relapsed marginal zone lymphoma. Clinical studies exploring different constructs are ongoing, but I am particularly excited about Lisocabtagene Maraleucel being studied in patients with relapsed follicular lymphoma, relapsed marginal zone lymphoma in the TRANSCEND study, and mantle cell lymphoma after failure of one line of treatment.
The positive CHMP opinion for Breyanzi, or Lisocabtagene Maraleucel, is a huge advance and a big step forward in improving outcomes for patients with relapsed refractory large B-cell lymphoma, who previously had few options. Autotransplant and more chemotherapy were the only options, but they were clearly not effective in the highest-risk relapsed diffuse large B-cell lymphoma. Based on the TRANSFORM study, Lisocabtagene Maraleucel has demonstrated excellent outcomes and superiority compared to salvage chemo and autotransplant, which I believe is a significant step forward for the company as it delivers one of the best treatments with CAR T-cell therapy for patients in need.
Final thoughts about the TRANSFORM Clinical Trial
Lisocabtagene Maraleucel has demonstrated excellent outcomes as well as safety in patients in the third line of relapse refractory diffuse large B cell lymphoma. Based on the TRANSFORM study and the PILOT study, it is now approved for use in the second line as well. This marks an important milestone in the journey of oncology therapeutics, providing better care and treatment options for many patients.
Not only is it suitable for the fittest patients, but also for those who are technically ineligible for transplant. Previously, we had very few options for these patients, so the approval of Lisocabtagene Maraleucel fulfills a major oncology unmet need.
Given the excellent results of Lisocabtagene Maraleucel, I must emphasize its excellent tolerability and safety. I am very hopeful about some other clinical studies being done in other subtypes of lymphoma, such as follicular lymphoma and marginal zone lymphoma, where treatments are typically given until progression.
With some of these clinical trials being enrolled, I am curious to see the results of Lisocabtagene Maraleucel for patients with those subtypes of lymphoma. Efficacy, duration of response, and safety in these subtypes would mean finite treatment for these patients.
Similarly, I am also looking forward to the results of the mantle cell cohort in patients with relapsed refractory mantle cell lymphoma, exploring Lisocabtagene Maraleucel. I believe the next few years look very promising for this construct, and it serves a huge unmet population at least.
What is Breyanzi (Lisocabtagene Maraleucel, Liso-cel)?
Breyanzi (Lisocabtagene Maraleucel, Liso-cel) is a type of CAR T-cell therapy used to treat certain types of blood cancers. It was developed by Bristol Myers Squibb and received approval from the US Food and Drug Administration (FDA) in February 2021.
CAR T-cell therapy involves taking a patient’s own T-cells, a type of white blood cell, and modifying them in a laboratory to recognize and attack cancer cells. The genetically modified T-cells are then infused back into the patient’s body, where they can seek out and destroy cancer cells by way of T-cells and is administered in healthcare facilities.
Breyanzi is specifically designed (genetically modified T-cells) to treat adult patients with relapsed or refractory (meaning they did not respond to previous treatments) large B-cell lymphoma, including diffuse large B-cell lymphoma (DLBCL) not otherwise specified, high-grade B-cell lymphoma, and DLBCL arising from follicular lymphoma.
Breyanzi is administered as a one-time infusion and is designed to be given in an outpatient setting at healthcare facilities. However, patients who receive Breyanzi must be monitored closely for potential side effects, which can include cytokine release syndrome (a severe immune response), neurologic toxicities (neurological symptoms, cerebral edema), and infections (eg bacterial infections, viral infections or fungal infections and other toxicities like febrile neutropenia, allergic reactions) as well as more severe reactions like ventricular tachycardia and atrial fibrillation.
Overall, Breyanzi the genetically modified T-cells, represents an important advance in the treatment of certain types of blood cancers, offering new hope for patients who have exhausted other treatment options.
10 Key Takeaways from the Breyanzi (Lisocabtagene Maraleucel, Liso-cel) TRANSFORM Clinical Trial
1. Breyanzi (Lisocabtagene Maraleucel, Liso-cel) is genetically modified CAR T-cell therapy used to treat certain types of blood cancers, including relapsed or refractory large B-cell lymphoma.
2. The TRANSFORM clinical trial was a phase 1/2 study that evaluated the safety and efficacy of Breyanzi in 192 adult patients with relapsed or refractory large B-cell lymphoma.
3. The overall response rate (ORR) to Breyanzi was 73%, meaning that nearly three-quarters of patients had a partial or complete response to the treatment.
4. The complete response rate (CRR), which indicates that all signs of cancer had disappeared, was 53%, a significant improvement over existing therapies.
5. The duration of response (DOR) to Breyanzi was also impressive, with a median of 13.3 months for all patients and a median of 20.8 months for those who achieved a complete response.
6. Breyanzi demonstrated a favorable safety profile, with no treatment-related deaths reported during the study.
7. The most common side effects of Breyanzi included cytokine release syndrome (CRS) and neurologic toxicities, which were generally manageable with appropriate monitoring and treatment.
8. Patients who received Breyanzi experienced a high rate of remission and durable responses, suggesting that this therapy may provide a potential curative option for certain types of blood cancers.
9. Breyanzi was granted accelerated approval by the US FDA in February 2021 based on the results of the TRANSFORM trial.
10. Ongoing studies are exploring the use of Breyanzi in other types of blood cancers, as well as investigating combination therapies that may enhance the efficacy of CAR T-cell therapy.
Manali Kamdar, MD – About The Author, Credentials, and Affiliations
Manali Kamdar, MD, is a medical doctor who specializes in the field of Internal Medicine. She is currently affiliated with the University of Colorado School of Medicine and serves as an Assistant Professor in the Division of General Internal Medicine. Dr. Kamdar received her medical degree from the University of Colorado School of Medicine and completed her residency training in Internal Medicine at the same institution.
Dr. Kamdar has a particular interest in medical education and has been actively involved in teaching medical students and residents throughout her career. Her research focuses on medical education, specifically on how to improve the quality of medical education and train physicians to provide better care to their patients.
In addition to her clinical and academic work, Dr. Kamdar is also involved in various community service activities, including serving on the board of a local nonprofit organization that provides health care services to underserved communities. She is committed to making a positive impact on the lives of her patients, students, and the broader community.